Over 780,000 strokes occur annually in the U.S. with at least 125,000 directly related to large vessel cerebrovascular atherosclerosis. Atherosclerosis is a complex genetic disease in which diabetes, hyperlipidemia and other vascular risk factors result in endothelial injury leading to an inflammatory response. Although the general inflammatory cascade has been described, specific pathophysiological mediators of the response-to-injury mechanisms in atherogenesis are not known. Identification of genes and pathways involved in atherosclerosis in an established porcine model of atherosclerosis is expected to elucidate the pathogenesis of human atheroselerosis and lead to specific therapeutic interventions that reduce the burden of cerebrovascular disease. Our central hypothesis is that genes coding for pro- and counter-inflammatory mediators will be differentially expressed in atherosclerotic and pre-atherosclerotic cerebral vessels compared with normal vessels favoring a pro-inflammatory protein profile. The Specific Aims of this proposal are to 1) Characterize a new large animal model of carotid and intracranial atherosclerosis, the diabetic/hyperlipemic pig simultaneously testing the effect of insulin treatment on atherosclerosis, 2) identify the genomic, proteomic and functional activities of key mediator molecules during the cerebrovascular atherogenesis (12 lipoxygenase, interleukin-1 receptor antagonist and monocyte chemotactic protein-I), and 3) identify differentially expressed genes in atherosclerotic, pre-atherosclerotic, and normal cerebral and precerebral vessels. The training goals are to broaden the principal investigator's education in basic stroke research on inflammatory and genetic mechanisms, to develop his expertise in gene expression and molecular basis of atherosclerosis, and to facilitate his development of a research team. Upon completion, we expect to have narrowed the range of candidate inflammatory genes associated with cerebrovascular atherosclerosis and related to vascular risk factors. This data will allow informed selection of candidate genes for future case-control studies. Collectively, these outcomes will associate previously suspected and novel inflammatory mediators with atherogenesis and plaque progression providing potential targets for treatment of this disease and prevention of its devastating complications, including stroke.